Glucocorticoid adjusts peripheral glucose metabolism and amino-acid metabolism. In human being, glucocorticoid is produced in adrenal glands, and in addition, it is metabolized in peripheral tissues such as adipose tissue or liver. Since 11βHSD1 is an enzyme which converts inactive cortisone into activated cortisol and is expressed mainly in adipose tissue or liver, 11βHSD1 is believed to have some relations to the activation of glucocorticoid in adipose tissue or liver. Since cortisol shows promoting activities for fat accumulation to adipocyte and for gluconeogenesis in liver, 11βHSD1 is believed to contribute to the maintenance of homeostasis in whole body by adjusting peripheral glucose and lipid metabolism. On the other hand, 11βHSD1 activity in adipose tissue significantly increases in insulin resistance patients in human being, and 11βHSD1 activity is remarkably higher in visceral fat than that in subcutaneous fat. Visceral fat accumulation and development of abnormal glucose and lipid metabolism are suppressed on high-fat diet feeding in 11βHSD1 gene defect mice, and adipose cell-specific 11βHSD1-overexpressed mice show remarkable visceral fat-type obesity or abnormal glucose and lipid metabolism. This indicates that overactivation of 11βHSD1 is intimately related to visceral fat accumulation and development of metabolic syndrome in human and mice (Nonpatent Documents 1 and 2). In other words, suppression of gluconeogenesis in liver and fat accumulation in adipocyte, and improvement of glucose and lipid metabolism in whole body are expected by inhibiting this enzyme activity.
As far as the improvement of glucose metabolism, since it has been reported that 11βHSD1 activity in pancreatic β cells could contribute to the suppression of insulin secretion or 11βHSD1 activity in human muscle cells could have some relations to the suppression of glucose uptake of muscle cells, 11βHSD1 inhibitor has potential to remedy hyperglycemia directly.
11βHSD1 is also expressed in central nervous systems including hippocampus. It has been known that patients with Cushing's disease wherein glucocorticoid overexpresses and those whom a kind of synthetic glucocorticoids dexamethasone is administered show depression symptom. It has been also known that glucocorticoid receptor antagonist is effective for depression and manic depression, and it has been indicated that glucocorticoid in central nervous systems is intimately related to the expression of symptom of depression as well as manic depression (Nonpatent Documents 3 and 4). Since 11βHSD1 plays a role in the production of active glucocorticoid in central nervous systems, it has been expected that 11βHSD1 inhibitor would show effectiveness in the treatment of depression and manic depression.
Furthermore, 11βHSD1 is indicated to have much relation to the adjustment of cognitive function, since depositions of amyloid β protein which is strongly indicated to relate to Alzheimer's dementia have been caused in mice to which glucocorticoid have been administered for a long term, and it is recognized that age-related cognitive function loss is inhibited and the increase of cognition maintenance is increased in 11βHSD1 gene defect mice (Nonpatent Documents 5 to 7). The knowledge as shown above indicates that 11βHSD1 inhibitor is useful as a therapeutic agent of dementia including Alzheimer's dementia. It has been shown that 11βHSD1 functions in immunocytes, and 11βHSD1 inhibitor is expected to show therapeutic effectiveness in diseases caused by abnormal immune function.
Various 11βHSD1 inhibitors have been reported, and for example, Patent Document 1 discloses a compound of formula:
wherein R1 is hydrogen atom, hydroxyl, etc., Z is oxygen atom or sulfur atom, R2 is hydrogen atom, methyl, ethyl or isopropyl, or R2, Y and N adjacent thereto may form saturated C5-C8 ring, the ring may be optionally substituted by R3, R4 and/or R5, Y is a single bond, C1-C4 alkyl, etc., W is C4-C8cycloalkyl, etc., R3, R4 and R5 are independently hydrogen atom, halogen atom, etc. However, the compounds disclosed in Patent Document 1 do not have an 8-azabicyclo[3.2.1]octane-8-carboxamide skeleton, so they are structurally different from the present invention.
Compounds disclosed in Patent Documents 2 and 3 have been known as a compound having an azabicyclo skeleton. Patent Document 2 discloses an example compound of formula:
However, a compound of Example 17 is structurally different from the present invention in that it has 6-azabicyclo[3.2.1]octane-6-carboxamide and phenyl.
Patent Document 3 discloses a compound of formula:
wherein G1 and G2 are different and R2 or —N(R11)C(═X)-L1-R1, R1 is selected from the following group:
R2 is selected from phenyl, —C(O)-phenyl, benzyl and 5 to 6-membered heteroaryl, R6, R7, R8, R9 and R10 are each independently alkyl which may be optionally substituted by 1 to 5 halogen atoms, etc., R11 is hydrogen atom, etc., R12 is hydrogen atom, etc., R13 is halogen atom, etc., L1 is —C(R12)(R13)—, etc., X is oxygen atom or sulfur atom. However, a compound represented by A is structurally different from the present invention in that it is characterized by a structural feature that G1 is aryl or heteroaryl.
[Patent Document 1] WO 2007/068330 pamphlet
[Patent Document 2] WO 2007/130898 pamphlet
[Patent Document 3] WO 2009/114173 pamphlet
[Nonpatent Document 1] Saishin Igaku, vol. 62, pp. 83-90, 2007
[Nonpatent Document 2] Stimson et al., Minerva Endocrinology, 32, 141 (2007)
[Nonpatent Document 3] Schatzberg et al., European Journal of Pharmacology., 583, 358 (2008)
[Nonpatent Document 4] Herbert et al., Journal of Neuroendocrinology., 18, 393 (2006)
[Nonpatent Document 5] Yau et al., Proceedings of the National Academy of Sciences., 98, 4716 (2001)
[Nonpatent Document 6] Green et al., Journal of Neuroscience, 26(35), 9047 (2006)
[Nonpatent Document 7] Yau et al., The Journal of Neuroscience, 27 (39), 10487 (2007)